Diabetes affects over 17 million adults in the US alone and over half of those diagnosed will develop neuropathy. This can lead to impaired neurogenic and vascular response to injury, resulting in chronic wounds and amputations. The underlying pathophysiology of neurovascular dysfunction and the role it plays in wound healing has not been fully elucidated. The goal of this proposal is to characterize the role of neuropathy in wound healing. We hypothesize that neurovascular innervation is reduced in patients with diabetic neuropathy. This leads to diminished capillary reactivity and impaired neurovascular function. We also hypothesize that there is a direct correlation between diminished neurovascular density and slower rates of wound healing. We propose to study the role of neurovascular structure and function in wound healing in patients with diabetes and healthy control subjects. The specific aims are to: (1) develop a novel method to quantify cutaneous neurovascular and capillary structures; (2) establish the relationship between these structures and cutaneous vascular function; and (3) determine the relationship between neurovascular and capillary density and rates of wound healing in patients with diabetic neuropathy and healthy controls. The long-term objective of this study is twofold: (1) to quantify the role of neurovasculature in wound healing in diabetes as a foundation for the development of novel therapeutic interventions; and (2) to provide a structured training environment to prepare the applicant for a career as an independent clinical investigator. We will study patients with diabetic neuropathy and healthy controls. Neurovascular structure will be quantified using skin punch biopsies which serve as the wound and tissue source. Tissue will undergo immunohistochemical staining and nerve fiber and capillary structures will be quantified using a novel stereological system. Neurovascular function will be assessed using acetylcholine iontophoresis to elicit the vasomotor axon-reflex and blood flow will be measured using laser doppler flowmetry. Wound healing will be quantified with serial high-resolution magnified digital photography measuring size, epithelialization and rates of wound healing until healed. This proposal also incorporates a research training program of mentorship, resources and didactics designed to develop the applicant's skills as an independent clinical researcher. The sponsor, Dr. Freeman, is an established researcher in autonomic neurology who has pioneered quantitative techniques in the field. He has an extensive record of mentorship and his Autonomic and Peripheral Nerve Lab at BIDMC has the resources and expertise needed to train new researchers. The applicant will also engage in coursework on clinical research through the Harvard School of Public Health as well as Harvard Catalyst Colloquium Series seminars. Weekly research meetings, journal clubs and Longwood Neurology Grand Rounds will also be attended. PUBLIC HEALTH RELEVANCE: Diabetes affects over 17 million adults in the US alone and over 50% of these patients will develop neuropathy, a risk factor for impaired wound healing, chronic ulcerations and amputations. The relationship between neuropathy and wound healing is not well understood. This protocol will elucidate the effect of neuropathy on neurovascular structure and function and thereby determine the role played by neuropathy in impaired wound healing.